rs17003235

Variant names:

• chr4-78450320-C-T
• rs17003235
• NM_025074.7:c.6444C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_025074.7(FRAS1):​c.6444C>T​(p.Thr2148Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,613,304 control chromosomes in the GnomAD database, including 37,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3651 hom., cov: 32)
  • Exomes 𝑓: 0.21 (34198 hom.)
• Consequence: FRAS1 NM_025074.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.561
• Publications: 10 publications found

Genes affected

FRAS1 (HGNC:19185): (Fraser extracellular matrix complex subunit 1) This gene encodes an extracellular matrix protein that appears to function in the regulation of epidermal-basement membrane adhesion and organogenesis during development. Mutations in this gene cause Fraser syndrome, a multisystem malformation that can include craniofacial, urogenital and respiratory system abnormalities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

FRAS1 Gene-Disease associations (from GenCC):

• Fraser syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Fraser syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.03).
• BP6: Variant 4-78450320-C-T is Benign according to our data. Variant chr4-78450320-C-T is described in ClinVar as Benign. ClinVar VariationId is 261809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.561 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025074.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	NM_025074.7	MANE Select	c.6444C>T	p.Thr2148Thr	synonymous	Exon 45 of 74	NP_079350.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FRAS1	ENST00000512123.4	TSL:5 MANE Select	c.6444C>T	p.Thr2148Thr	synonymous	Exon 45 of 74	ENSP00000422834.2
	FRAS1	ENST00000915768.1		c.6444C>T	p.Thr2148Thr	synonymous	Exon 45 of 73	ENSP00000585827.1
	FRAS1	ENST00000682513.1		c.6444C>T	p.Thr2148Thr	synonymous	Exon 45 of 64	ENSP00000508201.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31858 AN: 151920 Hom.: 3653 Cov.: 32

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.0653

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.163 AC: 40697 AN: 249132 AF XY: 0.160

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.0956

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.00172

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.221

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.207 AC: 302420 AN: 1461266 Hom.: 34198 Cov.: 33 AF XY: 0.202 AC XY: 146852 AN XY: 726948

African (AFR) AF: 0.281 AC: 9392 AN: 33450

American (AMR) AF: 0.103 AC: 4601 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3057 AN: 26128

East Asian (EAS) AF: 0.00212 AC: 84 AN: 39696

South Asian (SAS) AF: 0.0738 AC: 6365 AN: 86252

European-Finnish (FIN) AF: 0.170 AC: 9056 AN: 53388

Middle Eastern (MID) AF: 0.116 AC: 670 AN: 5758

European-Non Finnish (NFE) AF: 0.232 AC: 257854 AN: 1111524

Other (OTH) AF: 0.188 AC: 11341 AN: 60360

GnomAD4 genome AF: 0.210 AC: 31872 AN: 152038 Hom.: 3651 Cov.: 32 AF XY: 0.202 AC XY: 15024 AN XY: 74310

African (AFR) AF: 0.277 AC: 11493 AN: 41444

American (AMR) AF: 0.155 AC: 2362 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3468

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5170

South Asian (SAS) AF: 0.0654 AC: 315 AN: 4820

European-Finnish (FIN) AF: 0.165 AC: 1740 AN: 10568

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14920 AN: 67972

Other (OTH) AF: 0.193 AC: 407 AN: 2110

Alfa AF: 0.217 Hom.: 2005

Bravo AF: 0.212

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.206

EpiControl AF: 0.211

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fraser syndrome 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.0
DANN	Benign	0.54
PhyloP100		-0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17003235; hg19: chr4-79371474;